Iron differentially stimulates translation of mitochondrial aconitase and ferritin mRNAs in mammalian cells. Implications for iron regulatory proteins as regulators of mitochondrial citrate utilization.
Utilization of mRNAs containing iron-responsive elements (IREs) is modulated by iron-regulated RNA-binding proteins (iron regulatory proteins). We examine herein whether iron differentially affects translation of ferritin and mitochondrial aconitase (m-Acon) mRNAs because they contain a similar but not identical IRE in their 5'-untranslated regions. First, we demonstrate that m-Acon synthesis is iron-regulated in mammalian cells. In HL-60 cells, hemin (an iron source) stimulated m-Acon synthesis 3-fold after 4 h compared with cells treated with an iron chelator (Desferal). Furthermore, hemin stimulated m-Acon synthesis 2-4-fold in several cell lines. Second, we show that iron modulates the polysomal association of m-Acon mRNA. We observed m-Acon mRNA in both ribonucleoprotein and polyribosomal fractions of HL-60 cells. Hemin significantly increased the polyribosomal association and decreased the ribonucleoprotein abundance of m-Acon mRNA in HL-60 cells. Third, our results indicate that iron differentially regulates translation of m-Acon and ferritin mRNAs. A dose response to hemin in HL-60 cells elicited a 2-2.4-fold increase in m-Acon synthesis within 5 h compared with untreated cells, whereas ferritin synthesis was stimulated 20-100-fold. We conclude that iron modulates m-Acon synthesis at the translational level and that iron regulatory proteins appear to differentially affect translation of IRE-containing mRNAs.
Schalinske
K L
KL
Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Chen
O S
OS
Eisenstein
R S
RS
D000154:Aconitate Hydratase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002951:Citrates / Q000378:metabolism; D005293:Ferritins / Q000235:genetics*; D007501:Iron / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D014407:Tumor Cells, Cultured
D002951:Citrates; D012333:RNA, Messenger; D005293:Ferritins; D007501:Iron; D000154:Aconitate Hydratase